A common limitation in the administration of parenteral products is the onset of pain in the site of injection, that may result from the active drug, the formulation components, or the total formulation. In the development of a parenteral product the attention is mainly focused on the chemical, physical and microbiological stability and on the general safety of the formulation, considering the route of administration, while pain at injection site, that is a negative peculiarity of injectable drug formulations, do not receive much consideration. This is mainly due to the lack in the number and type of models available to study the physiology and mechanisms of pain, the difficulty, variability and cost associated with the use of animal models to evaluate pain and the necessity to use subjective versus objective measures (which often involve extensive experimental set-ups) to evaluate the extent of pain either in animals or humans.
It is possible that a given formulation can cause tissue damage that results in pain at the injection site; in this case toxicity screening methods, like red blood cells hemolysis, or L6 myoblast cell line method, or the rodent in vivo muscle model, can give a rational approach to develop and select the optimal formulations with respect to the desired physicochemical properties and tissue tolerability (Brazeau G. A. et al., “Current perspectives on pain upon injection of drug”, Journal of Parm. Sciences, 87, 6, Jun. 1998).
If, in contrast, there is no indication of any type of tissue damage at the site of injection, before testing any injectable formulations in humans, it is useful to have methods to screen formulations early during development, for their potential to cause pain.
One of these methods is the rat paw-lick model, used as a rapid in vivo screening method for parenteral products, but not always results are obtained, which are subsequently confirmed by clinical data.